Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification

Zhipeng Lin, Uttam Dhawa, Xiaoyan Hou, Max Surke, Binbin Yuan, Shu-Wen Li, Yan-Cheng Liou, Magnus J. Johansson, Li-Cheng Xu, Chen-Hang Chao, Xin Hong () and Lutz Ackermann ()
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Zhipeng Lin: Georg-August-Universität Göttingen
Uttam Dhawa: Georg-August-Universität Göttingen
Xiaoyan Hou: Georg-August-Universität Göttingen
Max Surke: Georg-August-Universität Göttingen
Binbin Yuan: Georg-August-Universität Göttingen
Shu-Wen Li: Zhejiang University
Yan-Cheng Liou: Georg-August-Universität Göttingen
Magnus J. Johansson: AstraZeneca
Li-Cheng Xu: Zhejiang University
Chen-Hang Chao: Zhejiang University
Xin Hong: Zhejiang University
Lutz Ackermann: Georg-August-Universität Göttingen

Nature Communications, 2023, vol. 14, issue 1, 1-8

Abstract: Abstract Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C−H activations, these arene functionalizations generally require directing groups to enable the C−H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C−H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C−H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C−H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C−H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations.

Date: 2023
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DOI: 10.1038/s41467-023-39747-0

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